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Astrocyte connexin43 containing channels amplify CNS dysfunction in NeuroAIDS

含有通道的星形胶质细胞连接蛋白 43 会放大 NeuroAIDS 中的中枢神经系统功能障碍

基本信息

批准号：
8826812
负责人：
Eliseo A Eugenin
金额：
$ 37.1万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-07 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8826812
关键词：
Address Animal Model Animals Anti-Retroviral Agents Apoptosis Area Astrocytes Blood - brain barrier anatomy Brain Cell Death Cell surface Cells Central Nervous System Infections Characteristics Cognitive deficits Collaborations Communication Connexin 43 Cytoplasm Data Dementia Development Endothelial Cells Extracellular Space Functional disorder Gap Junctions Goals HIV HIV-1 Homologous Gene Human Immune Immune response Impaired cognition In Vitro Individual Infection Inflammation Inflammatory Investigation Knockout Mice Letters Life Mediating Microglia Microinjections Minor Molecular Mus Nervous System Physiology Nervous System Trauma Neuraxis Neurodegenerative Disorders Neurologic Neurologic Dysfunctions Neurons Neuropathogenesis Pathogenesis Pathway interactions Persons Play Population Prevalence Principal Investigator Production Proteins Public Health Publications Regulation Research Role Signal Transduction Techniques Time Toxic effect Universities Viral Virus Diseases antiretroviral therapy base gap junction channel health organization in vivo inhibitor/antagonist macrophage migration motor deficit motor impairment mouse model nervous system disorder neuroAIDS neuronal survival new therapeutic target novel programs research study success therapy development tool

项目摘要

DESCRIPTION (provided by applicant): As of 2010, an estimated 34 million persons worldwide were living with human immunodeficiency virus (HIV) infection (Word Health Organization and UN estimations). Early after primary infection, HIV enters the CNS and causes cognitive and motor impairment in 30-60% of infected individuals, even in the antiretroviral era. As infected individuals are living longer, the prevalence of neurological complications due to HIV CNS infection has increased. The cellular basis and mechanisms by which HIV-1 causes neuropathogenesis, or NeuroAIDS, are still not well understood. Astrocytes are key cells in the CNS that regulate BBB integrity, CNS inflammation, immune responses and neuronal survival. HIV only infects a small percentage of these cells and minimal to undetectable viral production is detected. Nevertheless, our data demonstrate for first time that HIV infected astrocytes, through gap junction channels and perhaps hemichannels, can amplify inflammation and CNS damage. We hypothesize that Cx43 containing gap junctions (GJ) and hemichannels (uHC) amplify intercellular signals generated in few HIV infected astrocytes to surrounding uninfected cells resulting in cellular toxicity, BBB disruption and secretion of DKK1 leading to the CNS dysfunction often observed in the HIV infected population even in the current antiretroviral era, where viral replication is minimal. To address this hypothesis we will expand upon our extensive Preliminary Studies demonstrating the participation of these channels in astrocyte, neuronal and blood brain barrier (BBB) dysfunction, as well in amplification of cell activation and inflammation in HIV infected astrocytes and in uninfected cells. These data will characterize novel pathways of HIV toxicity within the brain and will identify the role of these channels in CNS dysfunction. The results obtained from this proposal should indicate potential novel therapeutic targets to limit the devastating consequences of NeuroAIDS. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

描述（由申请人提供）：截至2010年，全球估计有3400万人感染人类免疫缺陷病毒（HIV）（世界卫生组织和联合国估计）。在初次感染后早期，HIV进入CNS并在30-60%的感染个体中引起认知和运动障碍，即使在抗逆转录病毒时代也是如此。随着感染者的寿命延长，HIV CNS感染引起的神经系统并发症的患病率也增加了。HIV-1引起神经发病机制或NeuroAIDS的细胞基础和机制仍然没有很好地理解。星形胶质细胞是中枢神经系统中调节血脑屏障完整性、中枢神经系统炎症、免疫反应和神经元存活的关键细胞。HIV仅感染这些细胞中的一小部分，并且检测到最小到不可检测的病毒产生。然而，我们的数据首次表明，HIV感染的星形胶质细胞，通过间隙连接通道，也许半通道，可以放大炎症和中枢神经系统损伤。我们假设含有间隙连接（GJ）和半通道（uHC）的Cx43将在少数HIV感染的星形胶质细胞中产生的细胞间信号放大到周围未感染的细胞，导致细胞毒性、BBB破坏和DKK 1分泌，导致即使在病毒复制最小的当前抗逆转录病毒时代，在HIV感染人群中也经常观察到CNS功能障碍。为了解决这一假设，我们将扩大我们广泛的初步研究，证明这些通道参与星形胶质细胞，神经元和血脑屏障（BBB）功能障碍，以及放大细胞活化和炎症在HIV感染的星形胶质细胞和未感染的细胞中。这些数据将表征脑内HIV毒性的新途径，并将确定这些通道在CNS功能障碍中的作用。从这个提议中获得的结果应该表明潜在的新的治疗靶点，以限制NeuroAIDS的破坏性后果。PHS 398/2590（Rev.06/09）